Isotopically nonstationary 13C metabolic flux analysis in resting and activated human platelets |
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Institution: | 1. Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, CO, 80401, USA;2. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63110, USA;3. Department of Bioengineering, University of Colorado, Aurora, CO, 80045, USA;4. Hemophilia and Thrombosis Center, University of Colorado, Aurora, CO, 80045, USA;5. Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplant, University of Colorado, Aurora, CO, 80045, USA |
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Abstract: | Platelet metabolism is linked to platelet hyper- and hypoactivity in numerous human diseases. Developing a detailed understanding of the link between metabolic shifts and platelet activation state is integral to improving human health. Here, we show the first application of isotopically nonstationary 13C metabolic flux analysis to quantitatively measure carbon fluxes in both resting and thrombin activated platelets. Metabolic flux analysis results show that resting platelets primarily metabolize glucose to lactate via glycolysis, while acetate is oxidized to fuel the tricarboxylic acid cycle. Upon activation with thrombin, a potent platelet agonist, platelets increase their uptake of glucose 3-fold. This results in an absolute increase in flux throughout central metabolism, but when compared to resting platelets they redistribute carbon dramatically. Activated platelets decrease relative flux to the oxidative pentose phosphate pathway and TCA cycle from glucose and increase relative flux to lactate. These results provide the first report of reaction-level carbon fluxes in platelets and allow us to distinguish metabolic fluxes with much higher resolution than previous studies. |
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Keywords: | Blood platelets Metabolic flux analysis Metabolomics Thrombin |
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